WO2020232190A1 - Inhibiteurs de protéine kinase et leurs utilisations pour le traitement de maladies et de problèmes de santé - Google Patents

Inhibiteurs de protéine kinase et leurs utilisations pour le traitement de maladies et de problèmes de santé Download PDF

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WO2020232190A1
WO2020232190A1 PCT/US2020/032784 US2020032784W WO2020232190A1 WO 2020232190 A1 WO2020232190 A1 WO 2020232190A1 US 2020032784 W US2020032784 W US 2020032784W WO 2020232190 A1 WO2020232190 A1 WO 2020232190A1
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nmr
mmol
mhz
cdcl
ripk3
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PCT/US2020/032784
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Gregory Cuny
Alexei Degterev
Sameer NIKHAR
Siddharth Balachandran
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University Of Houston System
Trustees Of Tufts College
Institute For Cancer Research D/B/A The Research Intitute Of Fox Chase Cancer Center
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Priority to CA3137869A priority Critical patent/CA3137869A1/fr
Priority to EP20729566.8A priority patent/EP3968991A1/fr
Priority to JP2021568650A priority patent/JP2022533182A/ja
Priority to AU2020275304A priority patent/AU2020275304A1/en
Priority to US17/595,406 priority patent/US20220194937A1/en
Publication of WO2020232190A1 publication Critical patent/WO2020232190A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • Protein kinases are important enzymes in cellular signal transduction. In many pathological conditions aberrant signal transduction occurs. Therefore, protein kinase inhibitors can be used as therapeutic agents for the treatment of various diseases.
  • Influenza A virus (IAV) infections account for up to 700,000 hospitalizations and 50,000 annual deaths in the US alone. Worryingly, even though highly pathogenic H5 and H7 strains of avian IAV are thus far limited in their spread between humans, they require only a small number of mutations to become transmissible.
  • the lung epithelium is a primary site of mammalian Influenza A virus pathology.
  • Influenza A virus is a negative- sense RNA vims of the family Orthomyxoviridae .
  • vims replication occurs within the gastrointestinal tract and is typically asymptomatic.
  • mammalian IAV strains replicate in the respiratory tract and produce symptoms ranging from mild cases of‘the flu’ to severe, sometimes lethal disease.
  • IAV infects epithelial cells along the entire respiratory tract. Transmission is associated with infection of the upper tract, whereas severe disease is associated with infection in the lower lung, with the extent of lung involvement correlating with disease outcomes in humans and animal models.
  • IAV As a lytic vims, IAV kills most lung cell types in which it replicates. But not all cell death by IAV is pathogenic. While programmed cell death is essential for early control of IAV replication and prevention of virus spread to the whole lung, the death of the lung epithelial layer is also one of the primary drivers of IAV infection-associated morbidity and mortalitylO. In particular, the loss of Type I airway epithelial cells (AECs, which are essential for gas exchange) above a threshold of -10% is strongly correlated with mortality in the mouse model of IAV infection. When cell death is well-controlled and apoptotic, it represents a host defense mechanism that limits both virus spread and immunopathology.
  • AECs Type I airway epithelial cells
  • Receptor-interacting protein kinase 3 (RIPK3) is a multi-functional protein involved in cell death pathways in various tissues.
  • RIPK3 kinase activity provides a protection in a variety of animal models of inflammatory and degenerative conditions, including sepsis, brain trauma, acute kidney injuries, lung injury associated with influenza (IAV) infection, atherosclerosis, and many others.
  • IAV influenza
  • RIPK3 was recently uncovered as a targetable signaling pathway that accounts for almost all IAV-activated pathogenic death in infected cells. This pathway is initiated when the host sensor protein DAI detects IAV genomic RNA and activates RIPK3 kinase.
  • necroptosis or programmed necrosis
  • RIPK3 also activates a parallel pathway of non-pathogenic cell death (apoptosis) that mediates vims clearance.
  • apoptosis non-pathogenic cell death
  • inhibitors of RIPK3 kinase function will be expected to ameliorate necrotic lung injury without affecting vims clearance, and potentially represent an entirely new strategy for treatment of IAV disease.
  • two separate studies showed that animals deficient in Ripk3 gene show resistance in the development of atherosclerosis due to the inhibition of macrophage cell death and systemic inflammation.
  • the present disclosure relates generally to compounds that demonstrate inhibitory activity of receptor interacting kinase 2 (RIPK2) inhibitory activity and/or Activin- like kinase 2 (ALK2) and/or receptor interacting kinase 3 (RIPK3).
  • RIPK2 receptor interacting kinase 2
  • ALK2 Activin- like kinase 2
  • RIPK3 receptor interacting kinase 3
  • RIPK2 mediates pro-inflammatory signaling and is an emerging therapeutic target in autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD) and multiple sclerosis.
  • RIPK2 inhibitors could provide therapeutic benefit in the treatment of these and other conditions.
  • Activin-like kinase 2 (ALK2) has been implicated in a number of diseases, such as bone disease (e.g. fibrodysplasia ossificans progressiva, ankylosing spondylitis), cardiovascular diseases (e.g. atherosclerosis and vascular calcification), some cancers (e.g. diffuse intrinsic pontine gliomas) and bums.
  • ALK2 Activin-like kinase 2
  • Many of these maladies also have an inflammatory component that could exacerbate the condition and/or worsen the clinical outcome.
  • Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit in the treatment of these and other conditions.
  • the RIPK3 inhibitors potently and specifically inhibit RIPK3-driven necroptosis. These molecules are based on a pyrido[2,3-d]pyrimidine scaffold and target the ATP- and allosteric Glu-out pockets of RIPK3. This series is already ⁇ 10-fold more potent than previously reported RIPK3 inhibitor compounds at inhibiting necroptosis in cells. Importantly, compounds are identified that block necroptosis but do so without toxicity.
  • This disclosure describes a targetable signaling pathway that accounts for almost all IAV-activated pathogenic death in infected cells.
  • This pathway is initiated when the host sensor protein DAI detects IAV genomic RNA and activates RIPK3 kinase.
  • RIPK3 then triggers a form of cell death called necroptosis (or programmed necrosis), responsible for much of the lung injury seen during IAV infection. Fascinatingly, eliminating necroptosis not only drastically reduces lung damage and improves animal survival, but does so without impeding vims clearance. This is because RIPK3 also activates a parallel pathway of non-pathogenic cell death (apoptosis) that mediates vims clearance.
  • inhibitors of RIPK3 kinase function will ameliorate necrotic lung injury without affecting virus clearance, and represent an entirely new strategy for treatment of IAV disease.
  • RIPK3 is the central mediator of IAV-triggered epithelial cell death, or necroptosis. Necroptosis is activated by virus and microbial infections (including IAV), several innate-immune signaling pathways (most notably TNF, interferons, TLRs), certain pro- inflammatory stimuli (e.g., asbestos, oxidized LDL), and genotoxic stress. For decades, it was believed that the cell death accompanying acute infection by IAV was unspecified apoptosis, autophagy, or simply the passive, unprogrammed consequence of infection by a‘lytic’ virus.
  • the necroptosis arm requires RIPK3 kinase activity and targets pseudokinase mixed lineage kinase domain-like (MLKL).
  • the apoptosis arm requires FAS- associated protein with death domain (FADD) and caspase-8, and proceeds without need for the kinase activity of RIPK3. From within the necrosome, RIPK3 phosphorylates and activates MLKL, which then oligomerizes and traffics to the plasma membrane where it punches holes in the membrane, triggering cell swelling and lysis. Such necroptotic lysis of the cell causes the release of‘danger-associated molecular patterns’ (DAMPs) into the extracellular space, and is considered highly inflammatory.
  • DAMPs ‘danger-associated molecular patterns’
  • RIPK3 can also activate a parallel pathway of apoptosis via caspase-8, which promotes viral clearance. Importantly, this pathway of apoptosis does not require the catalytic activity of RIPK3, and can actually be facilitated by RIPK3 kinase blockade.
  • FIG. 1 shows RIPK3-mediated cell death or nectroptosis pathways, including those activated by tumor necrosis factor (TNF) (left) and IAV (right).
  • TNF tumor necrosis factor
  • IAV IAV
  • RIPK3 kinase blockade can prevent inflammatory pathology without affecting virus clearance.
  • Mice deficient in the DAI-RIPK3 cell death pathway cannot control IAV spread in the lung and succumb to this vims, highlighting the importance of DAI-RIPK3 signaling in anti-IAV host defense.
  • the necrotic branch downstream of RIPK3 is not only redundant for viral clearance, but actively promotes epithelial degradation and inflammation ⁇
  • selectively blocking necroptosis downstream of RIPK3 will prevent pathology without affecting beneficial virus clearance, which will still proceed normally via caspase-8-mediated apoptosis.
  • RIPK3 -mediated necroptosis requires the kinase activity of RIPK3, and is therefore pharmacologically readily targetable by the use of RIPK3 kinase inhibitors.
  • a clinically viable RIPK3 small-molecule inhibitor will represent a promising new therapeutic avenue for IAV-triggered necrotic death, epithelial degradation, inflammation, and consequent lung injury as seen in FIG. 1, right side.
  • RIPK3-mediated necroptosis potently amplifies inflammation in a variety of chronic conditions, including atherosclerosis and many TNF-associated pathologies, and underlies lung damage during acute IAV infection and ARDS. Moreover, RIPK3 can directly activate inflammatory gene expression independent of cell death, highlighting its centrality to host inflammatory processes. In agreement, genetic ablation of RIPK3 in mice ameliorated development of atherosclerotic plaques, almost-completely abolished TNF-triggered inflammatory shock, strongly reduced injury arising from chronically produced TNF, and eliminated IAV-induced necrotic lung damage without affecting vims clearance.
  • RIPK3 has been implicated in lipid and lysosomal storage diseases, such as Neiman-Pick and Gaucher disease, respectively. RIPK3 also has a pathogenic role in auto-immune diseases, including multiple sclerosis and lupus. Activity of RIPK3 has also been implicated in neurogeneration in different tissues and disease paradigms, indicating it to be a target for a broad range of neurodegenerative diseases. RIPK3 has also been found as a target in a broad range of ischemia-reperfusion injuries, such as stroke, myocardial infarction, kidney, retinal and liver ischemia and others
  • the present disclosure relates to a new panel of RIPK3 inhibitors, which may be referred to as the UH15 series.
  • UH15 series These compounds are based on a pyrido[2,3- dlpyrimidine scaffold, structurally distinct from previous RIPK3 inhibitor molecules. Members of this series are ⁇ 10-fold more potent than other disclosed RIPK3 inhibitors at blocking necroptosis.
  • the present UH15 compounds block RIPK3 without triggering apoptotic activity, and thus without the toxicity of other RIPK3 inhibitors. For most indications (e.g., TNF pathologies), blocking RIPK3 necroptosis without concurrently activating apoptosis is ideal.
  • a RIPK3 inhibitor that can efficiently block necroptosis while concurrently potentiating apoptosis of infected cells will not only halt deleterious necrotic lung damage but will also accelerate eradication of vims.
  • induction of apoptosis must be limited to the infected cell (i.e., be stimulus-specific) or toxicity will ensue (as seen with the previous compounds).
  • the present RIPK3 inhibitors target RIPK3 necroptosis as a new therapeutic entry-point for IAV disease.
  • Seasonal and pandemic strains of IAV trigger necrotic lung damage that underlies both ARDS and viral/bacterial pneumonia, each of which remain major causes of morbidity and mortality, with few effective therapeutic options.
  • the ideal therapeutic for severe IAV disease is one that blocks RIPK3 -dependent necroptosis but does not impede (or perhaps even simultaneously promotes) non-inflammatory virus clearance via RIPK3-dependent apoptosis.
  • RIPK3 is central to multiple inflammatory diseases, besides those seen during IAV infection. These include both acute and chronic inflammatory conditions known to be driven by TNF, such as colitis and rheumatoid arthritis. Moreover, RIPK3 is essential for all known pathways of necroptosis, while the allied kinase RIPK1 (currently the focus of efforts by others) only participates in a subset of necroptotic pathways, such as those activated by TNF (see FIG. 1, right). RIPK3 inhibitors thus will have benefit in a wider range of acute and chronic inflammatory conditions than serve as anti-TNF approaches or RIPK1 inhibitors.
  • FIG. 1 shows diagrams of RIPK3 -mediated cell death pathways activated by IAV (left) and TNF (right).
  • FIG. 2 shows structures of exemplary protein kinase inhibitors, identified as UH15 analogs.
  • FIG. 3 shows structures of exemplary RIPK3 inhibitors.
  • FIG. 4 shows a general overall synthetic scheme for exemplary preferred compounds disclosed herein as inhibitors of protein kinase activity, referred to generally as UH15 analogs, or UH15s.
  • FIG. 5 shows steps in the synthesis of an exemplary RIPK3 inhibitor.
  • FIG. 6 shows steps in the synthesis of an exemplary RIPK3 inhibitor.
  • FIG. 7 shows steps in the synthesis of an exemplary RIPK3 inhibitor.
  • FIGs. 8-9 show synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3.
  • FIG. 10 shows structures for intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3.
  • FIG. 11 shows a synthetic scheme for intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3.
  • FIGs. 12-13 show structures for intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3.
  • FIGs. 14-15 show synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3.
  • FIG. 16 shows structures for intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3.
  • FIG. 17 shows a synthetic scheme for exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIGs. 18-21 show structures for exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIGs. 22-23 show synthetic schemes for exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIG. 24 A shows a synthetic scheme for exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIG. 24B shows structures of intermediate compounds used in the synthesis of exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIG. 25 shows structures of exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIGs. 26-30 shows synthetic schemes for exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • FIG. 31 shows activity of select UH15 compounds and GSK’872 in blocking RIPK3 and MLKL phosphorylation in RAW264.7 macrophages.
  • the present disclosure relates to protein kinase inhibitors and uses thereof.
  • FIG. 1 The following figure depicts general structures of preferred embodiments of compounds that inhibit protein kinases, including receptor interacting kinase 2 (RIPK2), Activin-like kinase 2 (ALK2), and receptor interacting kinase 3 (RIPK3).
  • RIPK2 receptor interacting kinase 2
  • ALK2 Activin-like kinase 2
  • RIPK3 receptor interacting kinase 3
  • A can be N or CH.
  • R1 can be Me, , or
  • R2 can be Me, Et, Et-O-Me, or isobutyl.
  • R 3 can be where Et is ethyl.
  • FIG. 2 Additional preferred embodiments of compounds that inhibit RIPK2, ALK2, and RIPK3 are shown in FIG. 2.
  • ALK2, and RIPK3 are shown below.
  • R2 is Et (UH15-4), Et-O-Me (UH15-6), or isobutyl (UH15-10), and where X is F (UH15-18) or Me (UH15-20).
  • R can be H, or R can be a substituent on any one available position of the phenyl ring that is SO 2 Me,
  • E can be N, CH, or C-R, with R defined as above.
  • B and C can independently be N, CH, or C-Cl.
  • R 1 can be H, or R 1 can be C-Cl, C-F, C-OCH 3 , C-C(CH 3 ) 3 , or C-OH at any one available position of the ring.
  • a and D can independently be N or CH.
  • E can be N, CH, or C-R.
  • B and C can independently be N, CH, or C-Cl.
  • alkylhydroxyl including but not limited to 2-hydroxyethyl, alkylalkoxyl, including but not limited to 2-methoxyethyl, or alkylaryl, including but not limited to benzyl or phenethyl.
  • R can be H, where Me is
  • R 1 can be any alkyl group, including but not limited to methyl, ethyl, or propyl, or R 1 can be any aryl group, including but not limited to naphthyl, thienyl, indoyl, and the like.
  • R 3 can be H, or R 3 can be C-Cl, C-F, C-OCH 3 , C-C(CH 3 ) 3 , or C-OH at any one available position of the ring.
  • exemplary compounds that inhibit protein kinases including receptor interacting kinase 2 (RIPK2), Activin-like kinase 2 (ALK2), and receptor interacting kinase 3 (RIPK3), described herein may occur in different geometric and enantiomeric forms, and both pure forms and mixtures of these separate isomers are included in the scope of this invention, as well as any physiologically functional or pharmacologically acceptable salt derivatives or prodrugs thereof. Production of these alternate forms would be well within the capabilities of one skilled in the art.
  • the current invention also pertains to methods of prevention or therapy for inflammatory and degenerative conditions, including diseases involving protein kinase activity, such as Influenza A virus (IAV) infections and inflammatory conditions driven by TNF, including the step of administering a compound that inhibits protein kinase activity in accordance with preferred embodiments disclosed herein.
  • the methods of prevention or therapy for inflammatory or degenerative diseases involving protein kinase activity include the step of administering a compound that is a compound shown in FIG. 2 or in FIG. 3.
  • a pharmaceutical composition including a therapeutically effective amount of a compound that inhibits protein kinase activity as defined above and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser.
  • A“therapeutically effective amount” is to be understood as an amount of an exemplary protein kinase inhibitor compound that is sufficient to show inhibitory effects on protein kinase activity.
  • the actual amount, rate and time-course of administration will depend on the nature and severity of the disease being treated. Prescription of treatment is within the responsibility of general practitioners and other medical doctors.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, such as cutaneous, subcutaneous, or intravenous injection, or by dry powder inhaler.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such as gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • isotonic vehicles such as sodium chloride solution, Ringer’s solution, or lactated Ringer’s solution.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included as required.
  • salt any acid or base derived salt formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isoethonic acids and the like, and potassium carbonate, sodium or potassium hydroxide, ammonia, triethylamine, triethanolamine and the like.
  • prodrug means a pharmacological substance that is administered in an inactive, or significantly less active, form. Once administered, the prodrug is metabolised in vivo into an active metabolite.
  • the term“therapeutically effective amount” means a nontoxic but sufficient amount of the drug to provide the desired therapeutic effect.
  • the amount that is“effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular concentration and composition being administered, and the like. Thus, it is not always possible to specify an exact effective amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Furthermore, the effective amount is the concentration that is within a range sufficient to permit ready application of the formulation so as to deliver an amount of the drug that is within a therapeutically effective range.
  • FIG. 4 shows a general overall synthetic scheme for exemplary preferred compounds disclosed herein as inhibitors of protein kinase activity, referred to generally as UH15 analogs, or UH15s.
  • UH15 analogs or UH15s.
  • compounds may be referred to in the format of, for example, UH15-1 or UH15_1. These compounds have different structures.
  • UH15-15 is a different compound from UH15_15.
  • NMR spectra were recorded at room temperature using a JEOL ECA- 500 (1H NMR and 13C NMR at 400, 500 and 600 MHz) with tetramethylsilane (TMS) as an internal standard. Chemical shifts (d) are given in parts per million (ppm) with reference to solvent signals [1H-NMR: CDCl 3 (7.26 ppm), CD 3 OD (3.30 ppm), DMSO-d 6 (2.49 ppm); 13C-NMR: CDCl 3 (77.0 ppm), CD 3 OD (49.0 ppm), DMSO-d 6 (39.5 ppm)].
  • A21 was synthesized by using the using adaptation of the methods described in Cuny, et al. WO 2018/213219.
  • reaction mixture was then partitioned between ethyl acetate and water, dried over anhydrous Na 2 SO 4 , filtered, concentrated and purified by column chromatography using silica gel (20 % EtOAc/DCM) to give Nap-5 (23 mg, 36%) as light yellow solid.
  • FIGs. 8-9, 11, and 14-15 show synthetic schemes for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase, in accordance with preferred embodiments.
  • FIGs. 10, 12-13, and 16 show structures for intermediate compounds used in the synthesis of exemplary inhibitors of protein kinase, in accordance with preferred embodiments.
  • Ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (2) [0108] To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1) (100 mg, 0.43 mmol) in dry THF (2 mL) was added triethylamine (0.2 mL, 1.29 mmol) and ammonium hydroxide (0.5 mL). The resulting mixture was stirred at rt for 2 h till completion. After evaporation in vacuo to remove THF, the crude mixture then partitioned between H 2 O and EtOAc.
  • Method A Formic acid (1 mL) was added to 15a (100 mg, 0.48 mmol) in round bottom flask containing molecular sieves. The reaction mixture was heated at 60 °C for 6 h and then partitioned between saturated solution of NaHCO 3 and EtOAc. The organic layer was then washed with brine solution and then concentrated to give 16a (90 mg, 79%) as brown viscous liquid which was used directly into next step without purification.
  • 16c was prepared by method A where the reaction mixture was stirred at room temperature with overnight stirring. Yield 80%, white solid; 1 H NMR (400 MHz, DMSO- d6) d (ppm) 10.64 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 7.89-7.86 (m, 1H), 7.67-7.63 (m, 2H), 3.24 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) d 160.74, 141.95, 139.44, 130.80, 124.15, 122.51, 117.54, 44.08.
  • Method B To a round bottom flask fitted with reflux condenser was added 15d (200 mg, 0.72 mmol) and ethyl formate (1.16 mL, 14.4 mmol). TEA (0.15 mL, 1.08 mmol) was added to the above mixture and heated under reflux. After overnight stirring, solvent was evaporated, and the mixture was dissolved in DCM and extracted with water and brine solution. The extract was concentrated and purified by column chromatography using silica gel (30% EtOAc/Hexane) to get 16d (lOOmg, 45%) as colourless liquid.
  • Method C Formic acid (0.28 mL, 7.43 mmol) was added dropwise to acetic anhydride (0.60 mL, 6.37 mmol) maintained at 0 °C. The mixture was heated to reflux at 60 °C for 2 h to generate acetic formic anhydride reagent. The mixture was cooled to room temperature and 2 mL THF was added. 15e (200 mg, 2.12 mmol) dissolved in THF (1 mL) was added to acetic formic anhydride mixture and refluxed for another 2 h. Solvent was evaporated after completion, extracted in EtOAc/water system. Extract was concentrated and purified by column chromatography using silica gel (3% MeOH/DCM) to get 16e (173 mg, 67%) as white solid.
  • 16f was prepared by method C: Yield 75%, white solid.
  • FIG. 17 shows a synthetic scheme for exemplary inhibitors of RIPK3, compounds 17a-s (UH15’s).
  • FIGs. 18-21 show structures for exemplary inhibitors of RIPK3, in accordance with preferred embodiments.
  • 16a (30 mg, 0.13 mmol) and 14i (40 mg, 0.12 mmol) were used to make 17i.
  • 16a 22 mg, 0.09 mmol
  • 14k 20 mg, 0.05 mmol
  • 16a (16 mg, 0.07 mmol) and 141 (32 mg, 0.07 mmol) were used to make 171.
  • 16a 32 mg, 0.14 mmol
  • 14e 50 mg, 0,14 mmol
  • 16c (12mg, 0.06 mmol) and 14s (20 mg, 0.05 mmol) were used to make 17s.
  • 16a (8 mg, 0.03 mmol) and 14s (14 mg, 0.03 mmol) were used to make 17s * .
  • FIG. 22 shows a synthetic scheme for an exemplary inhibitor of protein kinase, compound UH15_32, in accordance with preferred embodiments.
  • Ethyl 6-chloro-4-(methylamino)nicotinate (52): [0324] To a solution of Ethyl 4,6-dichloronicotinate 51 (lOOmg, 0.45 mmol) in THF (3 mL) was added aqueous methyl amine (0.4 mL) at 0 °C and the mixture was stirred for 30 min at the same temperature. After 30 min the reaction mixture was stirred at room temperature for 2 h. Following completion the mixture was concentrated and purified by column chromatography using silica gel (10% EtO Ac/Hexane) to afford 52 (65 mg, 67%) as white solid.
  • FIG. 23 shows a synthetic scheme for an exemplary inhibitor of protein kinase, compound UH15_33, in accordance with preferred embodiments.
  • FIG. 24A shows a synthetic scheme for exemplary inhibitors of protein kinases and FIG. 24B shows the structures of intermediate compounds used in the synthesis of these exemplary inhibitors of protein kinases, in accordance with preferred embodiments.
  • FIG. 25 shows structures of exemplary inhibitors of protein kinases, in accordance with preferred embodiments.
  • FIG. 26 shows a synthetic scheme for exemplary inhibitors of protein kinase UH15PN 5 , in accordance with preferred embodiments.
  • FIG. 27 shows a synthetic scheme for an exemplary inhibitor of protein kinase UH15_25, in accordance with preferred embodiments.
  • reaction mixture was then partitioned between ethyl acetate and water, dried over anhydrous Na 2 SO 4 , filtered, concentrated and purified by column chromatography using silica gel (1.5 % MeOH/DCM) to give 60 (20 mg, 57%) as light yellow solid.
  • FIG. 28 shows a synthetic scheme for exemplary inhibitor of protein kinase UH15_36, in accordance with preferred embodiments.
  • reaction mixture was then partitioned between ethyl acetate and water, dried over anhydrous Na 2 SO 4 , filtered, concentrated and purified by column chromatography using silica gel (2.5 % MeOH/DCM) to give 71 (26 mg, 35%) as light brown solid.
  • FIG. 29 shows a synthetic scheme for exemplary inhibitor of protein kinase UH15_20, in accordance with preferred embodiments.
  • FIG. 30 shows a synthetic scheme for an exemplary inhibitor of protein kinase UH15_20, in accordance with preferred embodiments.
  • Reagents and conditions (a) TBSC1, imidazole, DMAP, DMF, 0 °C to rt, 4 h, 83%; (b) KF/AI 2 O 3 , DMA, rt, 2 h, 67%; (c) Pd2(dba)3, Xantphos, CS2CO 3 , 1,4-dioxane, 80 °C, 16 h, 47%.
  • Table 1 below shows the activities of select UH15 analogs.
  • IC 50 /LD50 values were determined for inhibition of recombinant RIPK3, inhibition of necroptosis in LPS/IDN- treated murine RAW264.7 macrophages and TNF/IDN-treated human Hela cells expressing RIPK3, RIPK3 binding by the inhibitors in live cells (NanoBRET assay), and induction of RIPK3 -dependent apoptosis (i.e., on-target toxicity).
  • Assays were performed using ADPGlo (kinase assay), CellTiter-Glo (viability), and NanoBRET (target engagement) assays.
  • the GSK’872 value shown is from Mandal et al. 2014.
  • recombinant RIPK3 protein (20 ng per reaction) is diluted in the reaction buffer consisting of 50 mM HEPES, pH 7.5, 50 mM NaCl, 30 mM MgC12, 1 mM DTT, 0.05% bovine serum albumin (BSA), 0.02% CHAPS.
  • Diluted protein is added to low volume white 384 well plates (2 mL/well).
  • Inhibitors are diluted in reaction buffer (final 25% DMSO), 1 mL is added to each well and incubated 5 min at room temperature. Reactions are initiated by the addition of 2 mL of 100 pM ATP in the reaction buffer.
  • IC 50 values are calculated based on a dose range of inhibitor concentrations using non-linear regression in GraphPad Prism software.
  • hTNFa Peprotech, Hela-R 3 cells
  • E.coli LPS E.coli LPS
  • 10 mM IDN6556 MedKoo
  • FIG. 31 shows that select UH15 compounds and GSK’ 872 block RIPK3 and MLKL phosphorylation in RAW264.7 macrophages.
  • Necroptosis was induced by the combination of LPS (10 ng/ml) and pan-caspase inhibitor IDN6556 (20 mM).
  • LPS is a TLR4 ligand that, like TNF, can activate RIPK3 (and necroptosis) in the presence of a caspase inhibitor.
  • the asterisk indicates a non-specific band sometimes see in pMLKL immunoblots. Samples are subjected to SDS-PAGE gele electrophoresis and Western blotting using RIPK3, phospho-Thr231/Ser232-RIPK3, MLKL and phospho-Ser345-MLKL antibodies (Abeam).
  • Table 2 shows stimulus-dependent (with TNF, 10 ng/ml) and -independent (without TNF) RIPK3 -dependent toxicity of select UH15 analogs.
  • Cell death was assessed by CellTiter-Glo assay. Toxicity was compared in Hela cells lacking RIPK3 and cells where RIPK3 was lentivirally re-expressed (Hela-RIPK3 cells).
  • RIPK2 Receptor interacting protein kinase 2
  • Recombinant RIPK2 protein (20 ng per reaction) is diluted in the reaction buffer consisting of 40 mM Tris (pH 7.5); 20 mM MgCl 2 ; 0.1 mg/mL BSA; 50 mM DTT. Diluted protein is added to low volume white 384 well plates (2 mL/well). Inhibitors are diluted in reaction buffer (final 25% DMSO), 1 mL is added to each well and incubated 5 min at room temperature. Reactions are initiated by the addition of 2 mL of 100 pM ATP and 1 mg/mL RS repeat peptide (SignalChem) in the reaction buffer. Plates are sealed with plastic coverslips and incubated at room temperature for 2 h.
  • ALK2 Activin-like kinase 2
  • Enzyme inhibitory activity was evaluated in a standard kinase enzyme assay by incubating human ALK2 with the protein substrate casein (1 mg/mL) and g- 33 ATR (10 pM) in the presence of various concentrations of test compounds (10 nM - 100 pM). After 30 min the amount of 33 P-casein was determined. A plot of inhibitor concentration verses % activity was constructed and from this plot an IC 50 value was determined.
  • HEK-Blue cells expressing human NOD2 and NFkB-SAEP reporter are seeded into 96 well clear plates at 7.5x10 3 cells per well in 100 mL of DMEM media supplemented with 10% FBS and 1% antibiotic-antimycotic mix. Cells are allowed to attach for 48 h in 5% CO 2 tissue culture incubator at 37 °C. On the morning of the experiment, media in the wells is replaced with 100 mL of HEK-Blue detection media (Invivogen). Cells are treated with the inhibitors, diluted in DMSO (0.5 mL per well) for 15 min in 5% CO 2 tissue culture incubator at 37 °C.
  • IC 50 values are calculated based on a dose range of inhibitor concentrations using non-linear regression in GraphPad Prism software.
  • Rodrigue-Gervais I.G. et al.
  • Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival. Cell Host Microbe 15, 23-35 (2014).

Abstract

La présente invention concerne des composés identifiés démontrant une activité inhibitrice de la protéine kinase. Plus spécifiquement, les composés sont mis en évidence pour inhiber la kinase 2 interagissant avec le récepteur (RIPK2) et/ou la kinase 2 de type activine (ALK2) et/ou la kinase 3 interagissant avec le récepteur (RIPK3). Les composés qui sont des inhibiteurs doubles RIPK2/ALK2 ou qui inhibent de préférence RIPK2 ou ALK2 pourraient fournir un bénéfice thérapeutique. Les composés qui fonctionnent en tant qu'inhibiteurs de RIPK3 fournissent un bénéfice thérapeutique dans le traitement des problèmes inflammatoires et dégénératifs.
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